Adenovirus vaccine vectors encoding SIV gag have been used to induce effective immunity against SHIV infection and disease in rhesus macaques. In ongoing clinical trials, adenovirus-based HIV vaccines induce HIV gag-specific CD8 and CD4 lymphocyte responses in human subjects. Adenovirus vectors thus show great promise as vehicles for HIV vaccination. However, many adults have been exposed to common adenoviruses, and have preexisting immunity to the adenovirus 5 (Ad5) and Ad2 vectors in present use. Preexisting antibody capable of adenovirus neutralization has been seen - both in animals and in human volunteers - to inhibit the effectiveness of adenovirus vectors in inducing HIV-specific immune responses. A possible solution to this problem is to use adenovirus vectors-- such as those derived from the chimpanzee adenovirus C68-- to which humans have not been exposed; C68-vectors resist neutralization by human sera, and have been effective as vaccine vehicles even in animals with high levels of Ad5-neutalizing antibody. However, the limited experience with C68 and its pathogenic potential, and concerns about its possible toxicities, may delay its clinical application. Neutralizing antibodies are serotype-specific, and recognize the surface of the major adenovirus capsid protein, hexon. The neutralizing epitopes are contained within surface loops whose sequences are highly variable among adenovirus serotypes; in contrast, the sequences that make up the base and interior of the hexon are highly conserved. We propose to replace the variable surface loops of the Ad5 hexon with those of C68 (in an experimental approach guided by available hexon crystal structures). This hexon-chimeric virus should be virtually identical to Ad5 in its biological and genetic properties-- and thus likely to be appropriate for clinical trial but resistant to neutralization by preexisting antibodies. Such a chimeric vector could solve one of the major obstacles to the use of adenovirus vectors for HIV immunization.